Overview of ovulation induction

INTRODUCTION — Ovulatory disorders can be identified in 18 to 25 percent of couples presenting with infertility [1]. Most of these women have oligomenorrhea, arbitrarily defined as menstruation that occurs at intervals of 35 days to six months. While ovulation may occasionally occur, spontaneous conception is unlikely.

This topic will review the efficacy of the different regimens used for ovulation induction in women with ovulatory disorders (clomiphene citrate, gonadotropins, pulsatile gonadotropin-releasing hormone [GnRH] therapy, aromatase inhibitors, and dopamine agonists) and provide our approach to the management of such women. Some of these drugs are reviewed in greater detail elsewhere, and ovarian stimulation for assisted reproductive technologies (ART) is also discussed elsewhere. (See "Ovulation induction with clomiphene citrate" and "Ovulation induction with letrozole" and "In vitro fertilization: Overview of clinical issues and questions".)

WOMEN WITH ANOVULATORY INFERTILITY — The clinical approach to ovulation induction requires an understanding of the causes of anovulation. Proper diagnosis of underlying conditions may not only be relevant for infertility treatment but may also have general health implications (such as bone health, brain health and wellbeing, sexual health, and long-term cardiometabolic health).

The four most common ovulatory disorders include polycystic ovary syndrome (PCOS), hypogonadotropic hypogonadism (HA), primary ovarian insufficiency (POI), and hyperprolactinemia (see "Clinical manifestations and evaluation of hyperprolactinemia"). Most experts have moved away from the World Health Organization (WHO) terminology which assign women to three categories of anovulation:

●WHO class 1 – Hypogonadotropic hypogonadal anovulation (hypothalamic amenorrhea [HA]) (see "Evaluation and management of secondary amenorrhea" and "Functional hypothalamic amenorrhea: Pathophysiology and clinical manifestations")

●WHO class 2 – Normogonadotropic normoestrogenic anovulation (almost all women in this category have polycystic ovary syndrome [PCOS]), when using the Rotterdam criteria for the diagnosis of PCOS [2]. This is the most common cause of anovulation. (see "Diagnosis of polycystic ovary syndrome in adults", section on 'Diagnosis')

●WHO class 3 – Hypergonadotropic hypoestrogenic anovulation (primary ovarian insufficiency [POI; premature ovarian failure]) (see "Clinical manifestations and diagnosis of primary ovarian insufficiency (premature ovarian failure)" and "Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)")

Hyperprolactinemia did not have a separate WHO category. The use of serum anti-müllerian hormone (AMH) concentrations may help to further define various patient categories. AMH levels are increased in PCOS and decreased in WHO class 1 and 3.

Hypogonadotropic hypogonadism — Hypothalamic causes of hypogonadotropic hypogonadism include functional hypothalamic amenorrhea (FHA) and isolated gonadotropin-releasing hormone (GnRH) deficiency. Multiple factors may contribute to the pathogenesis of FHA, including eating disorders (such as anorexia nervosa), exercise, and stress. Women in this group, which accounts for 5 to 10 percent of anovulatory women, usually have amenorrhea (although a range of menstrual dysfunction can be seen) [3]. (See "Functional hypothalamic amenorrhea: Pathophysiology and clinical manifestations" and "Epidemiology and causes of secondary amenorrhea".)

Biochemical findings include low serum estradiol concentrations and low or low-normal serum follicle-stimulating hormone (FSH) concentrations due to presumed decreased hypothalamic secretion of GnRH. AMH levels are low to normal under these circumstances. Reversing the lifestyle factors that contribute to the anovulation (low weight, excessive exercise, essentially any condition that leads to energy deficiency) should be attempted before considering ovulation induction with medications. (See "Functional hypothalamic amenorrhea: Pathophysiology and clinical manifestations" and "Epidemiology and causes of secondary amenorrhea".)

Although rare, hypogonadotropic hypogonadism presenting as primary amenorrhea can be due to complete congenital GnRH deficiency. This syndrome is called idiopathic hypogonadotropic hypogonadism or, if it is associated with anosmia, Kallmann syndrome. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)".)

Many infiltrative diseases and tumors of the hypothalamus and pituitary can also result in hypogonadotropic hypogonadism (due to diminished GnRH release or gonadotropin deficiency). (See "Causes of primary amenorrhea" and "Epidemiology and causes of secondary amenorrhea".)

Polycystic ovary syndrome — Women with PCOS constitute the largest group of anovulatory women encountered in clinical practice (70 to 85 percent of cases). Serum estradiol and FSH concentrations levels are normal, whereas luteinizing hormone (LH) concentrations may either be normal or elevated [4]. The criteria for diagnosis have been referred to as the "Rotterdam criteria" (table 1) [5]. Other criteria have also been described. (See "Diagnosis of polycystic ovary syndrome in adults", section on 'Diagnosis'.)

In women with obesity and PCOS, weight loss, which may restore spontaneous ovulation in many women, should be attempted before treatment with ovulation induction agents is considered [6]. In addition, women with PCOS should be screened for impaired glucose tolerance before starting ovulation induction because of the associated risk of pregnancy complications [7,8], suboptimal perinatal outcomes [9], and affected cardiometabolic child health [10]. (see "Treatment of polycystic ovary syndrome in adults" and "Pregestational (preexisting) diabetes mellitus: Obstetric issues and management")

There are differing opinions regarding the use of ovulation induction versus assisted reproductive technologies (ART) for the treatment of infertile women with PCOS [11]. Theoretical reasons to use in vitro fertilization (IVF) as first-line therapy include the ability to freeze all embryos and perform single embryo transfer, thereby reducing the major complications of infertility treatment: multiple pregnancies and ovarian hyperstimulation syndrome (OHSS). However, there is little evidence available to support this approach.

Primary ovarian insufficiency — POI, formerly referred to premature ovarian failure (POF) and defined as menopause before age 40 years, occurs in only 1 percent of all women but accounts for 5 to 10 percent of cases of anovulation. In most cases, the follicle pool is exhausted due to accelerated follicle loss of unknown origin (table 2) [12]. Many strategies, including pretreatment suppression with exogenous estrogen, GnRH agonists, or androgens, have been proposed with the aim of improving outcomes from ovulation induction, but none have been successful. An experimental approach with as yet uncertain benefits include the in vitro activation (IVA) of the patient's own ovarian tissue/oocytes [13]. The only effective option is IVF with donor oocytes. (See "Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)" and "Management of primary ovarian insufficiency (premature ovarian failure)" and "In vitro fertilization: Overview of clinical issues and questions", section on 'When are donor oocytes used?'.)

Women with POI have other important health issues related to their estrogen deficiency, including an increased risk of osteoporosis and cardiovascular disease if estrogen is not replaced. This is discussed in detail separately. (See "Management of primary ovarian insufficiency (premature ovarian failure)", section on 'Importance of estrogen therapy'.)

Hyperprolactinemic anovulation — Hyperprolactinemia accounts for 5 to 10 percent of women with anovulation. These women are anovulatory because hyperprolactinemia inhibits gonadotropin secretion, presumably by inhibiting GnRH. Most have oligomenorrhea or amenorrhea. Their serum gonadotropin concentrations are usually normal or decreased. (See "Clinical manifestations and evaluation of hyperprolactinemia".)

The presence of hyperprolactinemia should always be confirmed by several measurements of serum prolactin. Magnetic resonance imaging (MRI) of the head should be done in any woman with hyperprolactinemia in whom the cause is not obvious (eg, neuroleptic drug therapy, primary hypothyroidism). (See "Clinical manifestations and evaluation of hyperprolactinemia".)

OVERVIEW OF APPROACH

Goals — The overarching goals of ovulation induction in women with anovulatory infertility are:

●Induce monofollicular rather than multifollicular development and subsequent mono-ovulation and, ultimately, a singleton pregnancy and birth of a healthy newborn (figure 1). Focus on cumulative outcomes over a given period of time, rather than per cycle outcomes.

●Start with the least invasive, simplest, and cheapest treatment option; subsequent options should depend upon ovarian response (ovulation and number of follicles) (table 3).

●Maximize the rate of singleton pregnancies, minimize multiple gestation rates.

●Minimize the risk of ovarian hyperstimulation syndrome (OHSS) in women undergoing gonadotropin therapy, particularly those with polycystic ovary syndrome (PCOS), who are at higher risk. This could mean canceling the cycle and refraining from intercourse in case of multiple follicle development. (See "Prevention of ovarian hyperstimulation syndrome", section on 'Prevention of OHSS'.)

General principles

●The method of ovulation induction selected by the clinician should be based upon the underlying cause of anovulation and the efficacy, costs, risks, patient burden, and potential complications associated with each method as they apply to the individual woman.

●Women with ovulatory disorders should undergo conventional ovulation induction strategies before considering assisted reproductive technologies (ART) because success rates are good, and if monitored by an experienced clinician, complication rates are low [14-16].

●Induction of ovulation should be differentiated from stimulation of multiple follicle development in ovulatory women (currently referred to as ovarian stimulation [17]), as is done with assisted conception techniques, because the patient population, treatment goals, and clinical outcome are distinctly different.

●PCOS represents a risk factor for developing OHSS following ovarian stimulation with gonadotropins in any setting. (See "Prevention of ovarian hyperstimulation syndrome", section on 'Prevention of OHSS'.)

Preconception counseling — Like any couple planning fertility, couples considering ovulation induction should first undergo preconception counseling. Preconception care is a broad term that refers to the process of identifying social, behavioral, environmental, and biomedical risks to a woman's fertility and pregnancy outcome and then reducing these risks through education, counseling, and appropriate intervention. (See "The preconception office visit".)

In addition to a medical history and physical examination, the preconception assessment includes an assessment of rubella immunity and additional laboratory assessment based upon individual risk factors and local guidelines. (See "The preconception office visit", section on 'Laboratory assessment' and "Hemoglobinopathy: Screening and counseling in the reproductive setting and fetal diagnosis".)

In addition, genetic carrier testing is performed based upon the woman or partner's medical history or family history of heritable disease. (See "Cystic fibrosis: Carrier screening" and "Preconception and prenatal carrier screening for genetic disorders more common in people of Ashkenazi Jewish descent and others with a family history of these disorders".)

Serum anti-müllerian hormone (AMH) concentrations appear to be an early, reliable indicator of declining ovarian function. AMH is expressed by the small (<8 mm) preantral and early antral follicles, and serum concentrations reflect the size of the primordial follicle pool and may be the best biochemical marker of ovarian function across an array of clinical situations. AMH has been used as a predictor of ovarian response to stimulation for in vitro fertilization (IVF) success; low levels correlate with reduced ovarian reserve, while high levels correlate with a vigorous response to ovarian stimulation and a higher risk of OHSS (see "Female infertility: Evaluation", section on 'Anti-müllerian hormone'). AMH may also be a predictor of ovulation induction success, but it has not been well validated in this setting.

Patient-specific approach — The approach to ovulation induction depends upon the patient population; the different approaches are reviewed here briefly and in detail elsewhere:

●Functional hypothalamic amenorrhea (FHA) – Women with FHA are hypoestrogenemic and are therefore unlikely to respond to clomiphene citrate, an antiestrogen. However, because clomiphene citrate is easy to administer, it may seem reasonable to give one course of clomiphene prior to initiating pulsatile gonadotropin-releasing hormone (GnRH) or gonadotropin therapy. For those who ovulate, clomiphene citrate can then be continued. For those who do not ovulate, we suggest pulsatile GnRH as first-line therapy in countries where it is available. If pulsatile GnRH is unavailable, gonadotropin therapy should be initiated, with both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) (these women do not respond to FSH alone). (See 'Pulsatile GnRH therapy' below and 'Gonadotropin therapy' below and "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)", section on 'Ovulation induction in women'.)

●Polycystic ovary syndrome (PCOS) – The approach to women with PCOS starts with exercise and weight loss, if indicated, followed by ovulation induction. Weight loss should always be attempted in overweight or obese women with PCOS because ovulation can be restored with a modest amount of weight loss. For women with obesity and infertility who are >40 years of age, clinicians need to balance the health benefits of weight loss against the loss of fertility potential that might occur due to a delay in initiation of ovulation induction. Fertility potential declines rapidly after 40 years of age. (See "Treatment of polycystic ovary syndrome in adults", section on 'Weight loss'.)

Letrozole therapy, which results in higher live birth rates than clomiphene citrate in women with PCOS (especially those with obesity), is now considered first-line therapy. However, ovulation induction is an off-label use of letrozole, so some women prefer to use clomiphene citrate and, in some countries, letrozole is not available. (See 'Letrozole' below.)

●Primary ovarian insufficiency (POI) – All ovulation induction strategies for women with POI are unsuccessful, and we suggest against their use. Women with POI should be offered the option of IVF with donor oocytes as a successful way to fulfill their wish to have children. (See "Management of primary ovarian insufficiency (premature ovarian failure)" and "In vitro fertilization: Overview of clinical issues and questions", section on 'When are donor oocytes used?'.)

●The treatment of choice for anovulatory women with hyperprolactinemia is dopamine agonists; this is reviewed in detail separately. (See 'Dopamine agonists' below and "Management of lactotroph adenoma (prolactinoma) before and during pregnancy", section on 'Restoration of ovulation'.)

ORAL AGENTS

Letrozole — Letrozole, an aromatase inhibitor, blocks the conversion of testosterone and androstenedione to estradiol and estrone, respectively (unlike clomiphene, which blocks estrogen action), thereby reducing negative estrogenic feedback at the pituitary and thus increasing follicle-stimulating hormone (FSH) output (figure 2). In contrast to clomiphene citrate, letrozole appears to be free of the adverse effects on endometrial and cervical mucus attributed to clomiphene citrate [18]. (See "Ovulation induction with letrozole".)

For oligo-ovulatory women with polycystic ovary syndrome (PCOS) undergoing ovulation induction, we now suggest letrozole as first-line therapy over clomiphene citrate, regardless of the patient's body mass index (BMI). Before starting letrozole, the clinician must discuss that this use of the drug is not US Food and Drug Administration (FDA) approved and that there is an available alternative (clomiphene citrate). This recommendation is consistent with current American College of Obstetrics and Gynecology (ACOG) guidelines for choice of ovulation induction agents in women with PCOS [19].

A randomized trial [20] and a meta-analysis of 20 trials in nearly 4000 anovulatory women with PCOS [21] have both reported that letrozole results in higher live birth rates compared with clomiphene therapy. In contrast, clomiphene citrate is approved for ovulation induction and has been widely used for over 50 years [22]. Efficacy and safety of letrozole is reviewed in detail separately. (See "Ovulation induction with letrozole".)

Clomiphene citrate — In 1958, the nonsteroidal antiestrogen MER-25 was found to induce menstruation in an amenorrheic woman receiving the drug as an experimental treatment for endometrial cancer [23]. The next year, 43 anovulatory women given another antiestrogen, clomiphene citrate, also ovulated. Clomiphene, like tamoxifen and raloxifene, belongs to the category of compounds known as selective estrogen receptor modulators (SERMs). These drugs are competitive inhibitors of estrogen binding to estrogen receptors and have mixed agonist and antagonist activity, depending upon the target tissue. While they could be used for ovulation induction, tamoxifen and raloxifene are less effective than clomiphene, so are not typically used for this purpose.

Clomiphene citrate has been the most widely used agent for ovulation induction for over 50 years. Most, but not all, women with PCOS ovulate in response to clomiphene citrate. However, clomiphene is no longer considered to be first-line therapy for women with PCOS. (See 'Letrozole' above and "Ovulation induction with letrozole".)

Sixty to 85 percent of anovulatory women, typically with PCOS, ovulate in response to clomiphene citrate. Of those who ovulate, approximately 50 percent do so at a dose of 50 mg daily for five days, often cycle days 3 to 7. Twin and triplet gestations occur in approximately 7 to 9 and 0.3 percent, respectively, of clomiphene-induced pregnancies. The incidence of miscarriage and birth defects appears to be similar to that in spontaneous pregnancies, and the rate of ectopic pregnancy is probably not increased. The risk of ovarian hyperstimulation syndrome (OHSS) is less than 1 percent. (See "Ovulation induction with clomiphene citrate", section on 'Outcomes'.)

Predictors of ovulation in one study included a lower free androgen index (FAI), a calculation of testosterone not bound to sex hormone-binding globulin (SHBG), lower body mass index (BMI), presence of oligomenorrhea (as opposed to amenorrhea), and lower ovarian volume [24]. Of those who ovulate, 30 to 40 percent conceive. In the study noted [24], predictors of pregnancy with clomiphene included younger age, low BMI, low FAI, and oligomenorrhea rather than amenorrhea. A nomogram has been developed to help predict chances for live birth based upon simple, initial screening characteristics (figure 3). There is general agreement that women with obesity respond less favorably to clomiphene citrate ovulation induction.

Ovulation induction with clomiphene is reviewed in greater detail elsewhere. (See "Ovulation induction with clomiphene citrate" and "Treatment of polycystic ovary syndrome in adults", section on 'Ovulation induction medications'.)

Metformin — Correction of hyperinsulinemia with metformin has been shown to have a beneficial effect in anovulatory women with PCOS by increasing menstrual cyclicity and improving spontaneous ovulation. However, it does not appear to improve live-birth rates when given alone or in combination with clomiphene citrate. This topic is discussed separately. There is some experience with the use of another insulin-sensitizing drug, (myo)inositol. Results of well-designed studies of sufficient sample size should be awaited. (See "Metformin for treatment of the polycystic ovary syndrome", section on 'Anovulatory infertility'.)

Dopamine agonists — A dopamine agonist is the treatment of choice for women with hyperprolactinemic anovulation who are pursuing pregnancy. In women with a lactotroph adenoma, as an example, a marked reduction in the serum prolactin concentration occurs within two to three weeks (figure 4). (See "Management of lactotroph adenoma (prolactinoma) before and during pregnancy", section on 'Dopamine agonist therapy'.)

Bromocriptine is still sometimes used to restore ovulation in women with hyperprolactinemia. However, drugs that bind more specifically to dopamine D2 receptors on the lactotroph cells, such as cabergoline, are associated with fewer side effects. The fetal safety of bromocriptine is better established than cabergoline, but cabergoline appears to be safe as well. We typically let women choose which dopamine agonist they would like to try. Women who are especially concerned about the possibility of birth defects often choose bromocriptine, and women who are more concerned about nausea from bromocriptine typically choose cabergoline. (See "Management of lactotroph adenoma (prolactinoma) before and during pregnancy", section on 'Choice of dopamine agonist'.)

Dopamine agonist regimens and monitoring for ovulation induction are reviewed in detail separately. Treatment should be stopped once pregnancy has been diagnosed because the safety of continued usage has not been well established. During pregnancy, if a macroadenoma increases in size enough to cause visual field impairment, dopamine agonist therapy can be resumed. However, this is uncommon, as women with macroadenomas are counseled to avoid pregnancy until dopamine agonists are given to decrease its size (table 4) [25]. (See "Management of lactotroph adenoma (prolactinoma) before and during pregnancy", section on 'Patient counseling before pregnancy'.)

PULSATILE GnRH THERAPY — The pulsatile administration of gonadotropin-releasing hormone (GnRH) using an infusion pump stimulates the production of endogenous follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The resulting serum FSH and LH concentrations remain within the normal range, so the chances of multifollicular development and ovarian hyperstimulation are low. In comparison, continuous GnRH therapy lowers gonadotropin release (figure 5).

Indication — Pulsatile GnRH administration is indicated for women with hypogonadotropic hypogonadism (hypothalamic amenorrhea [HA]) who have normal pituitary function. Because pulsatile GnRH therapy maintains normal feedback mechanisms, most cycles result in a single dominant follicle. Therefore, rates of multiple gestation are extremely low, and the risk of ovarian hyperstimulation syndrome (OHSS) in women with HA is exceedingly low [15]. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)", section on 'Ovulation induction in women'.)

Pulsatile GnRH has also been used with some success for women with polycystic ovary syndrome (PCOS). This approach is counterintuitive as women with PCOS typically have an increased hypothalamic GnRH pulse frequency and high serum LH concentrations. (See "Treatment of polycystic ovary syndrome in adults", section on 'Ovulation induction medications'.)

Protocol — The intravenous (IV) route appears superior to the subcutaneous route. In order to mimic the normal pulsatile release of GnRH, the pulse interval is 60 to 90 minutes. The most physiologic dose for IV administration is 75 ng/kg [26] (in practice, some clinicians use 2.5 micrograms/pulse for women weighing <50 kg and 5 micrograms/pulse for women weighing >50 kg; others use doses ranging from 2.5 to 10 mcg per pulse, starting with 2.5 mcg and increasing until the minimum dose to induce ovulation is reached). In published studies, pulsatile GnRH is continued for the entire cycle. In the clinical setting, pulsatile GnRH administration may be discontinued after ovulation and the corpus luteum supported by human chorionic gonadotropin (hCG). A potential regimen for luteal phase hCG administration that has been used with gonadotropin therapy is 500 units administered on days 7, 10, and 13 after ovulation.

Women being treated with IV pulsatile GnRH should be seen weekly to monitor the IV site for swelling, pain, or erythema. We monitor the patient's initial cycles with ultrasound until we are confident that a dose that will induce ovulation has been reached. Serum estradiol monitoring is not necessary. Once ultrasound monitoring is stopped, the patient can predict ovulation in subsequent cycles with urinary LH kits. We confirm ovulation in subsequent cycles by measuring a luteal phase progesterone concentration.

Results — Ovulation rates of 90 percent and pregnancy rates of 80 percent or higher have been reported in women treated with pulsatile GnRH [15,27]. Local complications such as phlebitis may occasionally occur.

Pulsatile GnRH is currently unavailable in the United States but is widely used in other parts of the world. A smaller infusion device has been introduced.

GONADOTROPIN THERAPY — Since their introduction into clinical practice in 1961, gonadotropins extracted from the urine of postmenopausal women (human menopausal gonadotropins [hMG]), in which the ratio of luteinizing hormone (LH) to follicle-stimulating hormone (FSH) bioactivity is 1:1, have assumed a central role in ovulation induction [28]. Refinement of the initially crude preparation resulted in the availability of purified and highly purified urinary FSH (uFSH). Since 1996, recombinant human FSH (rhFSH, >99 percent purity) has been available. Recombinant preparations are appealing due to their ease of administration (subcutaneous rather than intramuscular), purity, and batch-to-batch consistency.

Candidates — There are several indications for gonadotropin therapy in anovulatory women:

●Women with polycystic ovary syndrome (PCOS) who have not ovulated or conceived with weight loss, clomiphene, or letrozole therapy (table 3).

●Hypogonadotropic anovulatory women with hypopituitarism or women with hypothalamic amenorrhea (HA) who do not have access to pulsatile gonadotropin-releasing hormone (GnRH) therapy. (See 'Pulsatile GnRH therapy' above.)

Preparations

hMG and FSH — The degree to which the type of follicle-stimulating hormone (FSH) compound employed may influence outcome of ovulation induction has been controversial. However, in a meta-analysis of 14 trials in 1726 women (10 trials comparing rhFSH and urinary gonadotropins [FSH-highly purified (HP) or human menopausal gonadotropins (hMG)] and four trials comparing FSH-purified [P] and hMG or HP-hMG), the following results were seen [29]:

●There were no differences in clinical pregnancy or live-birth rates for rhFSH and urinary-derived gonadotropins.

●There also were no differences between hMG preparations and urinary FSH-P.

●After pooling the data, there were no differences in the rates of ovarian hyperstimulation syndrome (OHSS) between rhFSH and urinary-derived gonadotropins.

●The evidence for all outcomes was of very low quality.

Purified uFSH has some LH activity, but rhFSH does not. The experience with rhFSH in hypogonadotropic hypogonadal women indicates that those women who have very low serum LH concentrations (<0.5 international units/L) need exogenous human chorionic gonadotropin (hCG) (or 75 international units/day subcutaneous recombinant LH) to maintain adequate estradiol biosynthesis and follicle development [30].

Long-acting rhFSH preparations are currently registered in some countries for use in in vitro fertilization (IVF) [31], but their use is not advised for ovulation induction.

Ovulatory triggers — hCG is used to trigger ovulation when the ovarian follicles are mature. Both urinary and recombinant hCG preparations are available. A dose of 250 mcg of recombinant hCG appears to be equivalent to the standard doses of urinary hCG (5000 to 10,000 units) [32].

Other ovulatory triggers, such as recombinant LH, are discussed elsewhere. (See "In vitro fertilization: Overview of clinical issues and questions".)

Protocols — The aim of ovulation induction with gonadotropins, as with clomiphene, is the formation of a single dominant follicle. In spontaneous cycles, this is achieved at the beginning of the cycle by a transient increase in serum FSH concentrations above the threshold value (figure 1) [33]. The concentrations then decrease due to negative feedback, preventing more than one follicle from undergoing preovulatory development (figure 6). Because ovarian sensitivity to FSH stimulation varies among individual women, specific treatment and monitoring protocols are needed to achieve development of a single follicle when exogenous gonadotropin is administered.

In the conventional gonadotropin protocol, the starting dose of FSH is 150 international units/day. However, this regimen is associated with a multiple pregnancy rate of up to 36 percent, and ovarian hyperstimulation occurs in up to 14 percent of treatment cycles [33].

In patients with PCOS, who are at particular risk for complications, this approach has been largely abandoned in favor of a low-dose, step-up protocol [34] designed to allow the FSH threshold to be reached gradually, minimizing excessive stimulation and therefore the risk of development of multiple follicles. In this protocol, the initial subcutaneous or intramuscular dose of FSH is 37.5 to 75 international units/day. It is recommended that the dose be increased only if, after 14 days, no response is documented on ultrasonography and serum estradiol monitoring. Increments of 37.5 international units then are given at weekly intervals up to a maximum of 225 international units/day (figure 7). The optimal interval for increasing the dose has not been well studied in PCOS patients.

The detection of an ovarian response is an indication to continue the current dose [35-37] until hCG can be given to trigger ovulation, as described below. (See 'Preparations' above.)

The low-dose, step-down protocol of ovulation induction mimics more closely the physiology of normal cycles [38]. Therapy with 150 international units FSH/day is started shortly after spontaneous or progesterone-induced bleeding and continued until a dominant follicle (>10 mm) is seen on transvaginal ultrasonography. The dose is then decreased to 112.5 international units/day followed by a further decrease to 75 international units/day three days later, which is continued until hCG is administered to induce ovulation. The appropriate starting dose can be determined by using the low-dose, step-up regimen for the first treatment cycle [39]. The robustness of the step-down regimen in everyday practice remains to be evaluated, and hence, the low-dose, step-up regimen should be considered the first choice treatment.

Monitoring — The ovarian response to gonadotropin therapy is monitored using transvaginal ultrasonography to measure follicular diameter. The scans during the late follicular phase, usually performed every two or three days, should be focused on identifying follicles of intermediate size.

hCG is given as an ovulatory trigger on the day that at least one follicle appears to be mature. The criteria for follicle maturity are a follicle diameter of 18 mm and/or a serum estradiol concentration of 200 pg/mL (734 pmol/L) per dominant follicle. Available hCG preparations are reviewed in the preceding section. (See 'Preparations' above.)

If three or more follicles larger than 15 mm are present, stimulation should be stopped, hCG withheld, and use of a barrier contraceptive advised in order to prevent multiple pregnancies and ovarian hyperstimulation. Measurements of serum estradiol are useful; preovulatory concentrations above the normal range may predict ovarian hyperstimulation. (See "Prevention of ovarian hyperstimulation syndrome" and "Strategies to control the rate of high order multiple gestation" and "Neonatal complications of multiple births".)

Serum progesterone measurements are sometimes useful before administration of hCG to determine if a premature LH surge has occurred, although we do not suggest routine progesterone measurements.

Outcomes

Pregnancy — A series of 225 women with PCOS treated over a 10-year period in one center found rates of ovulation and pregnancy of 72 percent and 45 percent, respectively, after use of the low-dose, step-up protocol [34]. Multiple folliculogenesis and ovarian hyperstimulation are less common than that seen with the standard protocol, and pregnancy rates appear similar [40-42]. However, the results of the low-dose, step-up protocol are negatively influenced by age and obesity.

Gonadotropin therapy after clomiphene treatment has failed has been the "classical" approach to ovulation induction for anovulatory infertility. Using this sequential approach, cumulative, singleton live-birth rates of 71 percent (only 7 percent multiples) over 24 months have been reported (figure 8) [14]. These results suggest that conventional approaches offer an effective means of treating the majority of women with anovulatory infertility before proceeding to more aggressive treatments such as IVF.

Ovulation induction is sometimes combined with intrauterine insemination (IUI). In the absence of male factor infertility, this clinical approach is not based on sound clinical evidence. If both anovulatory and male factor infertility are causing the couple's infertility, then combined ovulation induction with IUI is a useful approach.

Obesity and insulin resistance (but not an elevated serum LH concentration) are associated with lower success rates [14,43,44].

Multiple gestation — The risk of multiple gestation is increased with clomiphene citrate but to a much greater extent with gonadotropin therapy. The reasons for multiple gestation and strategies to lower risk are described in detail elsewhere [45]. (See "Neonatal complications of multiple births" and "Strategies to control the rate of high order multiple gestation", section on 'Limiting the multiple gestation risk of ovulation induction and superovulation'.)

Ovarian hyperstimulation syndrome — OHSS is a potentially life-threatening complication of ovulation induction. Its most severe manifestations include massive ovarian enlargement and multiple cysts, hemoconcentration, and third-space accumulation of fluid; these changes may be complicated by renal failure, hypovolemic shock, thromboembolic episodes, acute respiratory distress syndrome, and death [46-51]. This topic is reviewed in detail elsewhere. (See "Pathogenesis, clinical manifestations, and diagnosis of ovarian hyperstimulation syndrome" and "Prevention of ovarian hyperstimulation syndrome" and "Management of ovarian hyperstimulation syndrome".)

Adjuvant treatment — Adjuvant GnRH agonists or antagonists are commonly used for women with ovulatory infertility undergoing "ovarian hyperstimulation" with gonadotropins in the setting of IVF. The goal is to suppress pituitary gonadotropins to optimize control of the cycle and prevent a premature rise of endogenous LH prior to full maturation of the cohort of ovarian follicles. (See "In vitro fertilization: Procedure", section on 'Ovarian stimulation'.)

Similar strategies have been proposed to improve outcomes in anovulatory women undergoing ovulation induction with gonadotropins. However, insufficient data are available to conclude whether GnRH agonists may improve pregnancy or OHSS rates [52]. Similarly, there are insufficient data to draw conclusions regarding the possible role of GnRH antagonists as adjuvant therapy.

LAPAROSCOPIC OVARIAN DIATHERMY — Laparoscopic ovarian diathermy ("ovarian drilling") represents an alternative second-line therapy for women with polycystic ovarian syndrome (PCOS). In women who are still anovulatory despite an adequate trial of clomiphene citrate, another therapeutic option next to gonadotropins is laparoscopic surgery with electrocautery or laser. This topic is reviewed in detail elsewhere. (See "Treatment of polycystic ovary syndrome in adults", section on 'Laparoscopic surgery'.)

CANCER RISKS — Ovulation-induction drugs are used in virtually all fertility treatment regimens. All result in a temporary increase in serum concentrations of estrogen and progesterone. There have been concerns that this could affect the risk of hormone-sensitive cancers, but available data suggest that this is not the case. [53,54]

●Ovarian cancer – In some early studies, it appeared that the use of fertility drugs was associated with neoplasia, particularly borderline ovarian tumors [55-57]. Subsequent studies and meta-analyses have not confirmed an excess risk of ovarian cancer with infertility treatment (clomiphene or gonadotropin therapy), but in some reports, infertility itself was an independent risk factor [57-65] (see "Assisted reproductive technology: Pregnancy and maternal outcomes", section on 'Ovarian cancer and borderline tumors'). Thus, the initial observation that fertility drug use was linked to epithelial ovarian cancer appears to be explained by the fact that these drugs are more likely to be used in infertile women [56,66]. This hypothesis is supported by the observation that nulliparous women with refractory infertility may harbor a particularly high risk of epithelial ovarian cancer, irrespective of their use of fertility drugs [64,66-69].

The best evidence for a lack of association comes from a systematic review of 11 case-control studies and 14 cohort studies that included a total of 182,972 women. In this analysis, there was no convincing evidence of an excess risk of invasive ovarian tumors with fertility drug therapy [65]. However, there was a possible excess risk of borderline ovarian tumors in subfertile women undergoing in vitro fertilization (IVF), but there were methodological limitations, including a high risk of bias and small number of cases.

●Breast cancer – There does not appear to be an increased risk of breast cancer in women treated with fertility drugs [59,60,70-74]. However, interpretation of the available data is limited by several factors, such as survey information, small subgroup numbers, lack of evaluation by drug type/dose or cause of infertility, and confounding by the presence of other risk factors for breast cancer. (See "Factors that modify breast cancer risk in women".)

One relatively large, case-control study showed that infertile women with breast cancer were more likely to have been treated with human menopausal gonadotropin (hMG) for more than six cycles than infertile women without breast cancer; no increased risk was noted for clomiphene citrate [75]. However, this study was subject to many of the limitations noted above.

In contrast, in a prospective cohort study of 116,671 women with 1357 incident cases of breast cancer, women who reported infertility due to an ovulatory disorder had a lower risk of breast cancer than women who did not report infertility (hazard ratio [HR] 0.75) [76]; women who had received clomiphene citrate were at lowest risk (HR 0.60). In a sister-matched, case-control study among approximately 1400 women with and 1600 sisters without breast cancer, those who had used clomiphene citrate or exogenous follicle-stimulating hormone (FSH) but did not conceive were at lower risk of breast cancer compared with nonusers (odds ratio [OR] 0.62, 95% CI 0.43-0.89). Those who used fertility drugs and did conceive (at least a 10-week pregnancy) had the same breast cancer risk as women who had never taken fertility drugs [77].

Thus, women taking infertility drugs can be reassured that these drugs probably do not increase their risk of breast cancer, although it is not clear whether some subgroups may be at increased risk. Further investigation is required.

●Other ovulation induction drugs – Other ovulation induction therapies discussed below (including pulsatile gonadotropin-releasing hormone [GnRH] and dopamine agonists) have not been linked to ovarian or breast cancer risk.

●Colorectal cancer – Sex hormones may play a role in the etiology of colon cancer. Rates are higher in men compared with women, and exogenous estrogens (oral contraceptives and menopausal hormone therapy) have been associated with a slightly lower risk of colon cancer in some studies [78-80]. The impact of ovulation induction agents, which increase circulating estrogen levels, has not been well studied. However, in a population-based cohort study of nearly 150,000 women, no change in colon cancer risk was observed with the use of clomiphene citrate, exogenous gonadotropins, human chorionic gonadotropin (hCG), or GnRH agonists [81]. (See "Epidemiology and risk factors for colorectal cancer", section on 'Hormone therapy in females'.)

●Other cancers – In a retrospective, cohort study, neither clomiphene nor gonadotropin use appeared to be associated with an increased risk of melanoma, thyroid, or cervical cancers [82]. In contrast, the same investigators reported that clomiphene use may be associated with a greater risk of endometrial cancer. However, one explanation for these findings is that infertile women who used clomiphene were more likely to have underlying chronic anovulation, which is a strong risk factor for development of endometrial cancer. (See "Ovulation induction with clomiphene citrate", section on 'Cancer risks'.)

●Risk in offspring – A large, population-based study found that childhood tumor risk was not increased in children conceived following ovulation induction [83]. Ongoing monitoring of the long-term effects of these drugs is warranted since the number of cases was small. However, congenital malformation risk does not appear to be increased with oral ovulation induction agents (see "Ovulation induction with clomiphene citrate"). Pregnancy outcome after assisted reproductive technologies (ART) is discussed in detail elsewhere. (See "Assisted reproductive technology: Pregnancy and maternal outcomes".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Polycystic ovary syndrome" and "Society guideline links: Female infertility".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Infertility treatment with gonadotropins (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●General principles – Ovulatory disorders are a common cause of infertility, which in most cases is treatable with ovulation induction agents. The goal of therapy in these women is monofollicular development and subsequent ovulation. This approach should be differentiated from stimulation of multiple follicle development in ovulatory women, as is done with assisted reproductive technologies (ART). (See 'General principles' above.)

The method of ovulation induction selected by the clinician should be based upon the underlying cause of anovulation and the efficacy, costs, risks, burden of treatment, and potential complications associated with each method as they apply to the individual woman. (See 'General principles' above.)

●Hypogonadotropic hypogonadism

•Pulsatile GnRH – For women with hypogonadotropic amenorrhea, we suggest pulsatile gonadotropin-releasing hormone (GnRH) as first-line therapy in women with intact pituitary function in countries where it is available (Grade 2C). Because clomiphene citrate is easy to administer, it is reasonable to give one course of clomiphene prior to initiating pulsatile GnRH. However, very few women in this group respond.

•Gonadotropin therapy – If pulsatile GnRH is unavailable, gonadotropin therapy should be initiated, with both luteinizing hormone (LH) and follicle-stimulating hormone (FSH; these women do not respond to FSH alone). The low-dose, step-up regimen is considered to be the first-choice treatment. (See 'Patient-specific approach' above and 'Protocols' above.)

●Polycystic ovary syndrome (PCOS)

•Letrozole and clomiphene – For oligo-ovulatory women with PCOS undergoing ovulation induction, we suggest letrozole as first-line therapy over clomiphene citrate, regardless of the patient's body mass index (BMI) (Grade 2B). Before starting letrozole, the clinician must discuss that this use of the drug is not approved for ovulation induction. (See "Ovulation induction with letrozole", section on 'Suggested approach'.)

Doses, regimens, and monitoring for letrozole and clomiphene use in women with PCOS are discussed in detail elsewhere. (See "Ovulation induction with clomiphene citrate" and "Ovulation induction with letrozole".)

•Lifestyle changes – For women with obesity and PCOS, we also implement lifestyle changes and weight loss as an initial strategy to restore ovulatory cycles. (See "Ovulation induction with letrozole", section on 'Suggested approach'.)

•Gonadotropin therapy – If oral ovulation induction agents are unsuccessful in women with PCOS, then gonadotropin therapy should be started (in this case, FSH alone is sufficient). Strict attention to follicle number is essential to avoid multiple gestation and ovarian hyperstimulation. (See 'Gonadotropin therapy' above.)

To minimize the risk of multiple gestation and ovarian hyperstimulation syndrome (OHSS) in PCOS, gonadotropin treatment should be stopped if there are an excess number of follicles or extremely high serum estradiol concentrations. (See 'Monitoring' above and "Prevention of ovarian hyperstimulation syndrome" and "Strategies to control the rate of high order multiple gestation", section on 'Limiting the multiple gestation risk of ovulation induction and superovulation'.)

●Primary ovarian insufficiency – For women with primary ovarian insufficiency (POI; premature ovarian failure) no ovulation induction strategy has been shown to be effective. However, in vitro fertilization (IVF) with donor oocytes has high success rates. (See "In vitro fertilization: Overview of clinical issues and questions", section on 'When are donor oocytes used?'.)

●Hyperprolactinemia – For women with hyperprolactinemic anovulation, we suggest ovulation induction with dopamine agonists (Grade 2B). Although we typically start with cabergoline, bromocriptine is a reasonable choice as well. (See 'Dopamine agonists' above.)

●Cancer risks – While there has been concern about a possible increased risk of ovarian cancer with ovulation induction drugs, it appears that the risk may be due to the infertility itself rather than the medications used to treat it. However, because one study suggested an increase after 12 cycles of clomiphene citrate, women should not receive more than 12 cycles. There does not appear to be an increased risk of breast cancer or colon cancer with ovulation induction drugs. (See 'Cancer risks' above.)